P.77Repurposing of metformin identified as a potential therapy in models of BAG3 myofibrillar myopathy

Abstract

Dominant de novo mutations in the co-chaperone BAG3 cause a severe form of myofibrillar myopathy, exhibiting progressive muscle weakness, muscle structural failure, and protein aggregation. To identify therapies we generated two zebrafish models, one conditionally expressing BAG3P209L and one with a nonsense mutation in bag3. Whilst transgenic BAG3P209Lexpressing fish display protein aggregation, modelling the early phase of the disease, bag3−/− fish demonstrate impaired autophagic activity, exercise dependent fibre disintegration, and reduced swimming activity, consistent with later stages. Having confirmed the presence of impaired autophagy in patient samples we utilised the zebrafish model to screen a library of autophagy promoting compounds for their effectiveness at removing protein aggregates, identifying nine including Metformin. Further evaluation in our models demonstrated Metformin is not only able to remove the protein aggregates in zebrafish and human myoblasts, but is also able to rescue the fibre disintegration and swimming deficit observed in the bag3−/− fish. Therefore, repurposing Metformin provides a promising therapy for BAG3 myopathy. This study therefore illustrates an approach for the identification of treatments for rare neuromuscular diseases, using genetically matched animal models to identify mechanism, confirmation of this mechanism in patients, a targeted drug screen, and demonstration of efficacy in both an animal and human cell model, providing the necessary data for clinical translation of the findings.